Cyclic n-substituted derivatives of 1,4-benzene disulphonamide

ABSTRACT

AND THE SALTS THEREOF WITH PHARMACEUTICALLY ACCEPTABLE CATIONS WHEREIN N AND M ARE EACH TWO OR THREE; X is oxygen or sulphur; R2 and R3, when taken separately, are each hydrogen or alkyl having 1 to 4 carbon atoms; R2 and R3, when taken together, are alkylene having 2 to 4 carbon atoms; Y is methylene or a single bond; R4 and R5, when taken separately, are each hydrogen, hydroxy or alkoxy having 1 to 5 carbon atoms, and R4 and R5, when taken together, are oxo or alkylene dioxy having 2 to 4 carbon atoms, each oxygen atom in R4 and R5, when taken separately, and in R4 and R5, when taken together, being separated from the nitrogen atom of the heterocyclic ring by two or more carbon atoms, said compounds being cerebral vasodilators.   AND   Compounds of the formulae:

United States Patent [191 Holland Feb. 18, 1975 CYCLIC N-SUBSTITUTED DERIVATIVES OF 1,4-BENZENE DISULPHONAMIDE [75] Inventor: Gerald F. Holland, New London,

Conn.

[52] U.S. Cl. 260/293.73, 260/239 B, 260/243 B, 260/244 R, 260/247.1 R, 260/293.66,

260/327 R, 260/326.5 SF, 260/326.82,

[51] Int. Cl C07d 29/34 [58] Field of Search... 260/239 B, 293.73, 326.5 SF

[56] References Cited UNITED STATES PATENTS 3,165,550 1/1965 Holland et al. 424/32l Primary Examinerl-lenry R. .liles Assistant Examiner-S. D. Winters Attorney, Agent, or FirmConnolly and Hutz [57] ABSTRACT Compounds of the formulae:

H2NS s-N x (I) o o \(CH 3 v R and to R4 0 O /"(CH2) n n-s S-N Y (11) and the salts thereof with pharmaceutically acceptable cations wherein n and m are each two or three; X is oxygen or sulphur; R and R when taken separately, are each hydrogen or alkyl having I to 4 carbon atoms; R and R when taken together, are alkylene having 2 to 4 carbon atoms; Y is methylene or a single bond; R and R when taken separately, are each hydrogen, hydroxy or alkoxy having I to 5 carbon atoms, and R and R when taken together, are 0x0 or alkylene dioxy having 2 to 4 carbon atoms, each oxygen atom in R and R when taken separately. and in R and R when taken together, being separated from the nitrogen atom of the heterocyclic ring by two or more carbon atoms, said compounds being cerebral vasodilators.

8 Claims, No Drawings CYCLIC N-SUBSTITUTED DERIVATIVES OF 1,4-BENZENE DISULPHONAMIDE This invention relates to cyclic N-substitutcd derivatives of l,4-benzene disulphonamide which have cerebral vasodilator activity and are therefore useful for treating conditions attributable to a restriction of blood flow to the brain. Such conditions include atherosclerosis, occlusion of blooc vessels in the brain, stroke and other cerebrovascular diseases. Particularly useful compounds according to this aspect of the invention are those which have a selective effect on the cerebral vasculature, with a comparatively small effect on blood vessels in other tissues such as peripheral tissue and the kidneys, and so do not cause a serious fall in blood pressure or increase in diuresis.

The aforesaid derivatives include compounds of the formula 2 R 0 /(cH 2? fiv X (I) o o (c11 3 those of the formula 4 R 9 o (capm Z Q T "I (II) and the salts thereof with pharmaceutically acceptable cations wherein n and m are each two or three; X is oxygen or sulphur; R and R, when taken separately, are each hydrogen or alkyl having 1 to 4 carbon atoms; R and R, when taken together, are alkylene having Zto 4 carbon atoms; Y is methylene or a single bond R and R when taken separately, are each hydrogen, hydroxy or alkoxy having 1 to 5 carbon atoms and R and R when taken together, are oxo 0r alkylene dioxy having 2 to 4 carbon atoms, each oxygen atom in R and R when taken separately, and in R and R when taken together, being separated from the nitrogen atom of the heterocyclic ring by two or more carbon atoms.

Certain of the aforesaid compounds are old in the art as shown in US. Pat. No. 3,165,550. Those of the aforesaid compounds of the present invention which are unobvious include compounds of formula (I) and formula (ii) and the salts thereof with pharmaceutically acceptable cations wherein n and m are each 2 or 3-, X is oxygen or sulphur; R and R, when taken separately, are each alkyl having l to 4 carbon atoms; R and R, when taken together, are alkylene having 2 to 4 carbon atoms; Y is methylene or a single bond; R", when taken separately, is hydroxy or alkoxy having l to 5 carbon atoms; R, when taken separately, is hydrogen, hydroxy or alkoxy having I to 5 carbon atoms and R and R when taken together, are oxo or alkylene dioxy having 2 to 4 carbon atoms, each oxygen atom in R and R when taken separately, and in R and R when taken together, being separated from the nitrogen atom of the heterocyclic ring by two or more carbon atoms.

Preferred compounds of the invention having cerebral vasodilator activity are those of formula (I) in which X is an oxygen atom. Another preferred group are those in compounds of Formula (II) in which Y is a methylene group and R R together represent an oxo group or an alkylene dioxy group having 1 to 4 carbon atoms, each of these being attached to the methylene group, i.e. to Y. Another prefcrrcd group of compounds are those of formula (ll) wherein Y is methylene, R is hydroxy or alkoxy having 1 to 5 carbon atoms and R is hydrogen. Of those preferred compounds of formula (I) in which X is an oxygen atom, particularly preferred are those in which R and R are each alkyl having 1 to 4 carbon atoms. Of those preferred compounds in which Y is a methylene group, particularly preferred are those in which n and m are each 2, i.e., the heterocyclic ring is a 4-methoxypiperidene ring; a 4-hydroxypipcridene ring; a 4-piperidone ring or a dialkyl or alkylene ketal thereof.

The compounds of this invention, other than those in which R and R together are an oxo group, may be prepared from 4-sulphamoyl-benzene sulphonyl chlorides of the formula:

H2N-O2S- @so 01 by reaction with a cyclic amine of the formula:

(III) 2 (ca e or with a cyclic amine of the formula:

in a suitable solvent, e.g., acetone or dichloromethane, Preferably, the reaction is carried out in the presence of an excess of the amine reactant or in the presence of an equivalent amount of an organiz tertiary amine to remove the hydrochloric acid formed in the reaction. The reaction is completed in from i to 24 hours at 20C. or may be carried out at elevated temperatures, i.e., 30 to C. for periods of from I to 8 hours. The product may be isolated by simply adding the reaction mixture to normal aqueous hydrochloric acid solution, filtering, washing and recrystallizing from a suitable solvent.

The compounds of this invention may also be prepared from 4-nitrobenzene sulphonyl chloride by reac tion first with the cyclic amine of formula (IV) or (V) to form a compound of the formula:

1002 SO2N I- 2)n 3 or of the formula:

wherein R and R together, are not an oxo group, and the compound of formula (VI) or (Vll) is then reduced to the corresponding amine compound and the latter converted to the corresponding sulphamoyl compound by diazotization, treatment with sulphur dioxide in the presence of a cupric salt and then with ammonia.

Finally compounds in which r and R together are an oxo group are prepared from the corresponding dialkyl or alkylene ketals, i.e., compounds of formula (11) in which R and R are two alkoxy groups or an alkylene dioxy group attached to a single carbon atom, by meth ods well known in the art, e.g., by treatment with concentrated hydrochloric acid in aqueous dimethylformamide.

The salts ofthe present invention include those based on any pharmaceutically acceptable cation. The preferred pharm aceutically acceptable cations are those of the alkali metals, particularly sodium and potassium. Said salts are easily obtained in accordance with conventional methods. For example, the selected compound of formula (1) or formula (ll) is dissolved in an aqueous or alcoholic solution ofan alkali metal hydroxide such as sodium or potassium hydroxide and the resulting solution is simply concentrated.

In accordance with the treatment method of the present invention, the herein described compounds can be administered to an affected subject via the oral or parenteral route. Generally, there is a significant effect in increasing cerebral blood flow in cats, dogs and baboons at dose levels of from 2.5 to 25 mg/kg intravenously or from to 50 mg/kg orally when administered 3 times a day, the effect being cumulative. Although the physician will determine the precise dosage for a human patient, it generally will range from 0.5 to 100 mg/kg for intravenous administration and from 2 to 200 mg/kg for oral administration, each dosage form being'administered 4 times a day.

The compounds of the invention may be administered alone, but will generally be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice.

For administration orally in the form of tablets or capsules, it has been found advantageous to dissolve or disperse the compound in finely divided form (e.g., 30 microns or less in dimensions) in a matrix of a high molecular weight solid polyethylene glycol, e.g. a polyethylene glycol of average molecular weight 6,000 to 7,500 such as Carbowax 6,000. A non-ionic wetting agent as dispersion aid, e.g. a polyoxyethylene monostearate of average molecular weight about 1,000 such as Myrj 52, is preferably also included. For this type of formulation, the compound together with the dispersion aid may be dissolved in the molten polyethylene glycol and cooled, or alternatively may be mixed as an aqueous dispersion with the polyethylene glycol to form a paste and dried, and then, together with other excipients if desired, either granulated prior to compression into tablets or filled directly into capsules, by techniques well known in the art.

Alternatively, tablets may be formed in which a major part of the excipient is composed of a material which, when compressed, has a slower rate of dissolution than that normally achieved by standard tableting practice. Such materials include sugars and edible aminoacids such as glycine. The compound (in finely divided form) is preferably first mixed with the said material and then granulated with a comparatively small amount of the high molecular weight polyethylene glycol and a dispersion aid, before forming into tablets in the usual way.

For parenteral administration, the compounds, being acidic, are best used in the form of sterile aqueous solutions of their alkali metal (e.g. sodium) salts and such solutions may contain other solutes (e.g. sodium chloride) to ensure the stability of the solutions and their compatibility with body fluids, e.g. blood, when the compound is to be administered intravenously, intramuscularly or subcutaneously. The alkali metal salt solution may conveniently be formed by dissolving the compound (and any other solute required) in the sterile water and adjusting the pH to a value in the range from 10.5 to 12.0 with the appropriate alkali metal hydroxide.

The following examples illustrate preparation of the cerebral vasodilators of this invention.

EXAMPLE 1 4-(4-Methoxypiperidinosulfonyl) benzene sulfonamide To a solution of 25.6 g (0.1 mole) of 4-sulphamoyl benzene sulphonyl chloride in 250 ml. of acetone at room temperature was added portionwise 38 g. (0.3 mole) of 4-methoxypiperidine. The temperature rose to 50C. After stirring for one hour the solution was poured into 500 ml. of 1N hydrochloric acid. The product crystallized and the mixture was stirred for 30 min., filtered and washed well with water. After air drying, a recrystallization from acetone ml.)-hexane (250 ml.) yielded 22 g. (69% yield) of product, m.p. 187.5189.5C.

, The aforesaid chloride starting material was prepared by adding to a slurry of 172 g. (lmole) of sulfanilamide in 300 ml. of water at room temperature with stirring, ml. (2.1 mole) of concentrated aqueous hydrochloric acid. The resulting slurry was chilled to 0C in an acetone-dry ice bath, and then a solution of 72 g. (1.004 moles) of sodium nitrite, dissolved in 125 ml. water, was added from a dropping funnel at such a rate that the temperature never went above 5C. The addition required about one half hour during which. time ane yielded 69 g. (27% yield) of produce. m.p. the solid material dissolved to form (A). Liquid S l53l54.5C. from an inverted S0 cylinder, was added to 850 ml. of glacial acetic acid, which was cooled in ice, until the EXAMPLES n to XV weight increased by about 250 g. The solution was The compounds shown in Table l were prepared by placed in a 4 l. beaker, 68 g. (0.4 mole) of cupric chlothe method of Example I, using the appropriate cyclic ride dihydrate in water was added, and the mixture amine and 4-sulphamoyl-benzene sulphonyl chloride as cooled to 5C. The diazonium salt solution (A) was starting materials. then added with stirring, without ice cooling, as rapidly The compounds ofTable l are represented by the foras foaming would allow. Stirring was continued for ll) mula: min. after the addition was complete. The temperature of the reaction mixture rose to 30C. Two liters of Z Z water and ice were added and the mixture stirred. The product crystallized and stirring was continued for another minutes. The product was filtered and washed 15 well with cold water. After air drying, a recrystalli zation from 350 ml. of ethyl acetate and 700 ml. of hexozu'heterqcycle TABLE I Analysis Example W Theoretical in brackets 2a a a a.

II N 0 8' 46 36 5 73 8 35 CH3 III N6 I 144-5 43.20 5.60 8.47 (43.11 5.43 8 3 IV 9-0025 6 44 8 8 4 I I v O 177-78 4 .13 6.74 7.31

0011 V VI NO I 217 42.97 4.91 7.72 0011 (43.11 4.97 7.73)

VII 1 173-74 45.07 5.64 8.73

A 7 (45.28 5.70 8.80) VIII 6 I 214-216 16.84 6201 8127 MCI-I3 x N 0 1 4 .16 5.47 8.09 I Q 93 (43.11 5.43 8.38)

EXAMPLE XVl sulphon- Analysis: Found C. 4|.(14; H. 4.67; N. 8.54% Calculated for C H N O S C. 41.50; H. 4.40; N, 8.80)?

The activity of compounds of the invention as cerebral vasodilators is determined by the following method. Cats are anaesthetised with chloralose 80mg/kg, intravenously) after induction with halo- TABLE I (CONTINUED) 1 h t 1 0 Th ti i i b a 1; Exam e, N- e erocyc e m. eore C8. 11 rac e S L 75C 9m /OCH3 XII N 179-180 41.41 5.15 8.16

(41.14 5.18 8.00) QCH3 XIII 92-193 "91 7 4707 91 9 XIV N s 194-1955 37.81 4. 38 8.45

thane, nitrous oxide-oxygen (3:1 v/v). The animals are allowed to breathe normal room air and the rate and depth of respiration, heart rate and femoral arterial pressure are recorded. Electromagnetic flow probes are placed around the ipsilateral vertebral artery. Zero flow is established by momentarily occluding the arteries in order to calibrate the flow probes. The test compound (dissolved in N/IO sodium hydroxide in isotonic saline with warming and mixing and then back titration to pH 10 with dilute hydrochloric acid) is given at ID or 25 mg/kg via a femoral vein and readings are taken at intervals for up to 2 hours. Control observations after administration of the saline vehicle alone are also made. The criterion for selecting the preferred compounds is on the basis of increases in ipsilateral vertebral arterial flow at 10 mg/kg which are sustained over a period of 30 minutes as shown in Table ll. Blood flow is assessed by measuring the peak (systolic) pulsative flow and the mean pulsatile flow.

The products of Examples l, IX and XV have been found to give significant increases in peak and mean pulsatile flow at mg/kg. Table II hereinafter summarizes results obtained with representative cerebral vasodilators of the present invention in accordance with this method.

'mean maximum increase in blood flow (71 and duration of action in minutes it).

lVF ipsilatcral verte ral arterial flow.

EXAMPLE XVll Tablet formulation mg/tablet Active ingredient 100.0 glycine 320.7 PEG 6000 40.0 Myrj 52 20.0 magnesium stearate 4.9 gelatin 2.4

mean particle diameter (from surface area/g) less than 16 microns. polyoxyethylene glycol of mean molecular weight 6000. a foodstuffs quality surfactant: polyoxyethylene stearute.

EXAMPLE XVlll Capsule formulation mg/capsule Active ingredient 100.0 PEG 6000 280.0 Myrj 5 2 20.0 400.0

"' mean particle diameter less than 3 microns. and as in Example XVII.

The active compound is ball-milled in water to achieve the small particle size, mixed with the PEG 6000 and Myrj 52 as a paste and then dried at 40C. to form a powder which is then filled into capsules in the usual way.

EXAMPLE XIX Parenteral formulation mg/ml Active ingredient 7.5 sodium chloride 7.9

(sufficient in pH adjustment) sodium hydroxide (sufficient to make up volume) WllICl' 7 R4 0 0 (CH2)1 a n-s s-n Y 0 l3 (CH2) and the salts thereof with pharmaceutically acceptable cations wherein n and m are each 2 or 3; Y is methylene or a single bond; R when taken separately, is bydroxy or alkoxy having 1 to 5 carbon atoms; R when taken separately, is hydrogen, hydroxy or alkoxy having 1 to 5 carbon atoms; and R and R when taken together, are oxo, each oxygen atom in R and R when taken separately, and in R and R when taken together, being separated from the nitrogen atom of the heterocyclic ring by two or more carbon atoms.

2. The compound ofclaim 1 wherein Y is methylene.

3. The compound of claim 2 wherein R and R together represent an oxo group attached to said methylene group.

4. The compound of claim 3 wherein m and n are each 2.

5. The compound of claim 2 wherein R is alkoxy having I to 5 carbon atoms and R is hydrogen.

6. The compound of claim 5 wherein m and n are each 2.

7. The compound of claim 1 wherein m and n are each 2, Y is methylene, R is 4-methoxy and R is hydrogen.

8. The compound of claim 1 wherein m and n are each 2, Y is methylene, R is 4-hydroxy and R is hydro- 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF
 2. The compound of claim 1 wherein Y is methylene.
 3. The compound of claim 2 wherein R4 and R5 together represent an oxo group attached to said methylene group.
 4. The compound of claim 3 wherein m and n are each
 2. 5. The compound of claim 2 wherein R4 is alkoxy having 1 to 5 carbon atoms and R5 is hydrogen.
 6. The compound of claim 5 wherein m and n are each
 2. 7. The compound of claim 1 wherein m and n are each 2, Y is methylene, R4 is 4-methoxy and R5 is hydrogen.
 8. The compound of claim 1 wherein m and n are each 2, Y is methylene, R4 is 4-hydroxy and R5 is hydrogen. 